ABSTRACT The CF Cell & Tissue Bioassays Core (Core D) is an important component of the UCSF CF Research and Translation Core Center. The major objective of the Core is to test the efficacy of CF-targeted small molecules discovered by high-throughput screening (HTS; performed by Core A) in physiologically relevant pre-clinical assays. This objective is accomplished by performing electrophysiological and optical assays that probe ion channel and epithelial cell function in CF-relevant cell and tissue models. Assays use immortalized cell culture models, primary cell cultures derived from human sources, three-dimensional models including organoids, and tissue samples such as airway fragments from non-CF and CF subjects (provided by Core B, Cell & Tissue Models). The most heavily used resource in the Core are Ussing chambers for analysis of short-circuit current which is performed to validate hits identified by HTS, determine hit efficacy, provide structure-activity relationship data during hit-to-lead optimization, and assess lead efficacy in human airway tissue samples from CF and non-CF subjects. Other major Core D resources include optical assays of CF-relevant airway properties, including measurement of airway surface liquid and submucosal gland secretions in human cell cultures and airway tissues from CF and non-CF subjects. Many of the optical assays provided by Core D were developed to investigate CF lung disease mechanisms and are uniquely available at UCSF. Core D also carries out electrophysiological and optical assays to support basic and translational research on CF pathophysiology and assay development for screening. Of the 25 projects in the research base, 20 will use Core D resources.